Project Summary Problem statement: Asthma is one of the most common and burdensome of all chronic inflammatory diseases, causing almost lifelong respiratory symptoms to various degrees through a patient?s life due to severe airway inflammation, airway obstruction, and triggered hyper-responsiveness. Almost 10% of these individuals experience very severe, complex, and heterogeneous disease symptoms that remain intractable and treatment-resistant. Current therapy is often ineffective in severe asthma conditions. Importantly, long-term use of corticosteroids and long-acting ? agonists (LABAs) is associated with disabling side effects, leading to worsening of the disease and excess asthma-related mortality. There is thus a clear unmet need for novel therapies that can significantly improve outcomes over current standard of care. Innovation: New therapies to treat asthma include monoclonal antibodies targeting cytokines and receptors of the IL4/IL13/JAK/STAT6 pathway. The pathway has been validated in clinical trials of dupilimab, an antibody that targets IL-4R? receptor, and lebrikizumab, an anti-IL-13 antibody, among others. However, most biologics also have a significant risk of developing neutralizing immune reactions (anti-drug antibodies). Atrapos Therapeutics, LLC was founded in 2015 to develop and commercialize a first-in-class small molecule therapeutic technology developed by a team of academic scientists at the MD Anderson Cancer Center and Baylor College of Medicine. This technology uniquely targets a crucial intracellular pathway that drives the immune response in a host of chronic diseases, including asthma. The team successfully demonstrated the ability of the lead molecule (PM-43I) to significantly reduce the severity of established asthma in mice models. They also demonstrated the effectiveness of the molecule to prevent asthma in mice with no prior disease. An important differentiating factor from established immunosuppressant therapies in severe asthma (steroids) is the precision of the immunomodulation, whereby the antiviral immunity is unaffected, reducing the risk of secondary infections (a common problem with prolonged steroid therapy). Technology Development Status: We successfully met and expanded the Specific Aims of our Phase I proposal. PM-43I was shown to have activity primarily limited to the lung when delivered intranasally, and a greatly expanded toxicity assessment program unequivocally established the safety of the molecule at significantly high doses. Proposal: The long-term plan of this project is to develop PM-43I for clinical use in treatment of moderate to severe asthma. The goal of the work outlined in this grant proposal is to characterize, synthesize and test the drug product for this indication. Overall, the Specific Aims outlined in this proposal will help to complete the preclinical and product development work for PM-43I. While Atrapos has had some success in raising angel capital coupled with NIH funding, the successful awarding of this proposal would complete the remaining preclinical and product development of PM-43I required for regulatory (FDA and IRB) approvals for clinical translation.